The nuclear eicosanoid receptor, PPARgamma, is aberrantly expressed in colonic cancers.
Continuous use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the relative risk of colorectal cancer in humans and decreases tumor yield in rodents treated with carcinogens. One well documented target for NSAIDs is prostaglandin endoperoxide synthase (cyclooxygenase) and two isoforms of this enzyme have been identified, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX enzymes produce eicosanoid products, some of which have recently been shown to activate transcription mediated by the nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARgamma), whose expression is largely restricted to adipose tissue. The present study was undertaken to determine if PPARgamma was expressed in colonic tumors. PPARgamma messenger RNA (mRNA) and protein levels were assayed in colonic tumors and normal adjacent mucosa, as well as in a variety of human colon cancer cell lines. There was a marked increase in PPARgamma RNA levels in four out of four of the colonic tumors compared to paired normal mucosa, where little expression of PPARgamma was detected. Western blotting analysis showed that PPARgamma protein was expressed in four out of five colonic tumor samples. PPARgamma was also expressed in a subset of polyps, and in certain human colon cancer cell lines as well. Additionally, we were able to demonstrate that an eicosanoid, 15 deoxy-delta12,14 PGJ2, transactivated transcription of a PPRE-driven promoter in CaCo-2 cells. Thus, we have shown that PPARgamma gene and protein expression is elevated in rodent colon tumors, in selected human colon cancer cell lines and that the PPARgamma receptor is functional in CaCo-2 cells. Since PPARgamma is a ligand-modulated transcription factor, it may provide a novel target for chemopreventive strategies for colorectal cancer.
DuBois
R N
RN
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. duboisrn@aoi.com
Gupta
R
R
Brockman
J
J
Reddy
B S
BS
Krakow
S L
SL
Lazar
M A
MA
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015777:Eicosanoids / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D015777:Eicosanoids; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D001397:Azoxymethane